A path-integral Car-Parrinello molecular dynamics simulation of liquid water and ice is performed. It is found that the inclusion of nuclear quantum effects systematically improves the agreement of first-principles simulations of liquid water with experiment. In addition, the proton momentum distribution is computed utilizing a recently developed open path-integral molecular dynamics methodology. It is shown that these results are in good agreement with experimental data.

The transport of protons through aqueous, partially aqueous, or nonaqueous hydrogen-bonded media is a fundamental process in many biologically and technologically important systems. Liquid methanol is an example of a hydrogen-bonded system that, like water, supports anomalously fast proton transport. Using the methodology of ab initio molecular dynamics, in which internuclear forces are computed directly from electronic structure calculations as the simulation proceeds, we have investigated the microscopic mechanism of the proton transport process in liquid methanol at 300 K. It is found that the defect structure associated with an excess proton in liquid methanol is a hydrogen-bonded cationic chain whose length generally exceeds the average chain length in pure liquid methanol. Hydrogen bonds in the first and second solvation shells of the excess proton are considerably shorter and stronger than ordinary methanol–methanol hydrogen bonds. Along this chain, proton transfer reactions occur in an essentially random manner described by Poisson statistics. Structural diffusion of the defect structure is possible if the proton migrates toward an end of the defect chain, which causes a weakening of the hydrogen bonds at the opposite end. The latter can, therefore, be easily ruptured by ordinary thermal fluctuations. At the end of the chain where the proton resides, new hydrogen bonds are likely to form due to the strong associative nature of the excess proton. It is through this “snake-like” mechanism that the defect structure is able to diffuse through the hydrogen-bond network of the liquid. The estimated activation enthalpy of this proposed mechanism is found to be in reasonable agreement with the experimentally determined activation enthalpy.

Free-energy-based simulations are increasingly providing the narratives about the structures, dynamics and biological mechanisms that constitute the fabric of protein science. Here, we review two recent successes. It is becoming practical: (i) to fold small proteins with free-energy methods without knowing substructures, and (ii) to compute ligand-protein binding affinities, not just their binding poses. Over the past 40 years, the timescales that can be simulated by atomistic MD are doubling every 1.3 years – which is faster than Moore's law. Thus, these advances are not simply due to the availability of faster computers. Force fields, solvation models and simulation methodology have kept pace with computing advancements, and are now quite good. At the tip of the spear recently are GPU-based computing, improved fast-solvation methods, continued advances in force fields, and conformational sampling methods that harness external information.

Glasses are dynamically arrested states of matter that do not exhibit the long-range periodic structure of crystals 1-4 . Here we develop new insights from theory and simulation into the impact of quantum fluctuations on glass formation. As intuition may suggest, we observe that large quantum fluctuations serve to inhibit glass formation as tunnelling and zero-point energy allow particles to traverse barriers facilitating movement. However, as the classical limit is approached a regime is observed in which quantum effects slow down relaxation making the quantum system more glassy than the classical system. This dynamical 'reentrance' occurs in the absence of obvious structural changes and has no counterpart in the phenomenology of classical glass-forming systems.Although a wide variety of glassy systems ranging from metallic to colloidal can be accurately described using classical theory, quantum systems ranging from molecular, to electronic and magnetic form glassy states 5,6 . Perhaps the most intriguing of these is the coexistence of superfluidity and dynamical arrest, namely the 'superglass' state suggested by recent numerical, theoretical and experimental work [7][8][9] . Although such intriguing examples exist, at present there is no unifying framework to treat the interplay between quantum and glassy fluctuations in the liquid state.To attempt to formulate a theory for a quantum liquid to glass transition, we may first appeal to the classical case for guidance. Here, a microscopic theory exists in the form of mode-coupling theory (MCT), which requires only simple static structural information as input and produces a full range of dynamical predictions for time correlation functions associated with single-particle and collective fluctuations 10 . Although MCT has a propensity to overestimate a liquid's tendency to form a glass, it has been shown to account for the emergence of the non-trivial growing dynamical length scales associated with vitrification 11 . Perhaps more importantly, MCT has made numerous non-trivial predictions ranging from logarithmic temporal decay of density fluctuations and reentrant dynamics in adhesive colloidal systems to various predictions concerning the effect of compositional mixing on glassy behaviour 12,13 . These have been confirmed by both simulation and experiment [14][15][16] .A fully microscopic quantum version of MCT (QMCT) that requires only the observable static structure factor as input may be developed along the same lines as the classical version. Indeed, a zero-temperature version of such a theory has been developed and successfully describes the wave-vector-dependent dispersion in superfluid helium 17 . In the Supplementary Information, we outline the derivation of a full temperature-dependent QMCT. In the limit of high temperatures, our theory reduces to the hard-sphere fluid. φ is the volume fraction, Λ * = (βh 2 /mσ 2 ) 1/2 is the thermal wavelength in units of inter-particle separation σ , and β = 1/k B T is the inverse temperature. The approach by which the...

Ab initio molecular dynamics simulations are employed to study the structural and proton transport properties of methanol-water mixtures. Structural characteristics analyzed at two different methanol mole fractions (X(M) = 0.25 and X(M) = 0.5) reveal enhanced structuring of water as the methanol mole fraction increases in agreement with recent neutron diffraction experiments. The simulations reveal the existence of separate hydrogen-bonded water and methanol networks, also in agreement with the neutron diffraction data. The addition of a single proton to the X(M) = 0.5 mixture leads to an anomalous structural or Grotthuss-type diffusion mechanism of the charge defect in which water-to-water, methanol-to-water, and water-to-methanol proton transfer reactions play the dominant role with methanol-to-methanol transfers being much less significant. Unlike in bulk water, where coordination number fluctuations drive the proton transport process, suppression of the coordination number of waters in the first solvation shell of the defect diminish the importance of coordination number fluctuations as a driving force in the structural diffusion process. The charge defect is found to reside preferentially at the interface between water and methanol networks. The length of the ab initio molecular dynamics run (approximately 120 ps), allowed the diffusion constant of the charge defect to be computed, yielding a value of D = 4.2 x 10(-5) cm2/s when deuterium masses are assigned to all protons in the system. The relation of this value to excess proton diffusion in bulk water is discussed. Finally, a kinetic theory is introduced to identify the relevant time scales in the proton transfer/transport process.

A key factor influencing a drug's efficacy is its residence time in the binding pocket of the host protein. Using atomistic computer simulation to predict this residence time and the associated dissociation process is a desirable but extremely difficult task due to the long timescales involved. This gets further complicated by the presence of biophysical factors such as steric and solvation effects. In this work, we perform molecular dynamics (MD) simulations of the unbinding of a popular prototypical hydrophobic cavity-ligand system using a metadynamics-based approach that allows direct assessment of kinetic pathways and parameters. When constrained to move in an axial manner, the unbinding time is found to be on the order of 4,000 s. In accordance with previous studies, we find that the cavity must pass through a region of sharp wetting transition manifested by sudden and high fluctuations in solvent density. When we remove the steric constraints on ligand, the unbinding happens predominantly by an alternate pathway, where the unbinding becomes 20 times faster, and the sharp wetting transition instead becomes continuous. We validate the unbinding timescales from metadynamics through a Poisson analysis, and by comparison through detailed balance to binding timescale estimates from unbiased MD. This work demonstrates that enhanced sampling can be used to perform explicit solvent MD studies at timescales previously unattainable, to our knowledge, obtaining direct and reliable pictures of the underlying physiochemical factors including free energies and rate constants.ligand unbinding | kinetics | enhanced sampling | dewetting transition T he unbinding of ligands from host substrates is a phenomenon widely occurring across biological and chemical sciences. It is of great interest to be able to understand the thermodynamics and kinetics of such processes, especially how they are influenced by solvent and steric effects. An accurate estimate of unbinding kinetics is in fact of crucial importance for drug discovery paradigms (1, 2). However, despite the advent of massively parallel computer resources, it has not been so easy to simulate the dynamics of ligand unbinding and calculate associated rate constants. The complications are mainly twofold. First, as has been seen in studies of model systems (3-10), various proteins (11-13), HIV (14), and actual anticancer drugs (15-17), the solvent often manifests itself at the molecular scale. Whereas coarse-grained models can be fit to explicit solvent molecular dynamics (MD) simulations (3), predictive power can be attained only by performing all-atom MD. Second, performing all-atom MD for unbinding of such systems is however plagued by the timescale problem. MD is restricted to integration timesteps of a few femtoseconds, which can be partially mitigated by multiple timestep MD algorithms (18). However, it is not yet routinely feasible to go into the millisecond regime and beyond for any system with more than a few thousand atoms.In this paper we consider a popular prototy...

Acetonitrile confined in silica nanopores with surfaces of varying functionality is studied by means of molecular dynamics simulation. The hydrogen-bonding interaction between the surface and the liquid is parametrized by means of first-principles molecular dynamics simulations. It is found that acetonitrile orders into bilayer like structures near the surface, in agreement with prior simulations and experiments. A newly developed method is applied to calculate relevant time correlation functions for molecules in different layers of the pore. This method takes into account the short lifetimes of the molecules in the layers. We compare this method with prior techniques that do not take this lifetime into account and discuss their pitfalls. We show that in agreement with experiment, the dynamics of the system may be described by a two population model that accounts for bulk-like relaxation in the center and frustrated dynamics near the surface of the pore. Specific hydrogen-bonding interactions are found to play a large role in engendering this behavior.

A model of protein-ligand binding kinetics, in which slow solvent dynamics results from hydrophobic drying transitions, is investigated. Molecular dynamics simulations show that solvent in the receptor pocket can fluctuate between wet and dry states with lifetimes in each state that are long enough for the extraction of a separable potential of mean force and wet-to-dry transitions. We present a diffusive surface hopping model that is represented by a 2D Markovian master equation. One dimension is the standard reaction coordinate, the ligand-pocket separation, and the other is the solvent state in the region between ligand and binding pocket which specifies whether it is wet or dry. In our model, the ligand diffuses on a dynamic free-energy surface which undergoes kinetic transitions between the wet and dry states. The model yields good agreement with results from explicit solvent molecular dynamics simulation and an improved description of the kinetics of hydrophobic assembly. Furthermore, it is consistent with a "non-Markovian Brownian theory" for the ligand-pocket separation coordinate alone.hydrophobicity | hydrodynamics | non-Markovian effects | dewetting transitions R ecent theoretical work has shown that the displacement of water by drug molecules is important in the thermodynamics and kinetics of ligand-enzyme binding (1-3). The kinetics of drug docking is a key metric for lead optimization (4). Presently, we explore the kinetic motifs of hydrophobic association on ligand binding. This is achieved by developing a simple model for hydrophobic association that is compared with explicit solvent molecular dynamics (MD) simulation.One of the signature features of hydrophobic assembly is the observation of a dewetting transition (5-9). Drying plays an important role in protein self-assembly and the behavior of nanoconfined water (10, 11). The present paper draws on our extensive work on the role of molecular-scale hydrodynamics in hydrophobic collapse (12, 13), where we showed that when the attraction between water and two associating nanoscale objects is weak, assembly proceeds via a drying transition in the intersolute region. This transition is characterized by large peaks in the relative translational friction coefficient that correspond to large and slow solvent fluctuations. The slow relaxation times exhibited by water undergoing dewetting transitions suggest that nonMarkovian effects may prove to be a crucial element in a full description of the assembly kinetics.We presently extend our earlier investigations to a model of a spherical ligand docking in a concave cavity. The model is similar to one investigated in a series of papers by McCammon and coworkers (14,15), but is altered to describe the assembly of a nanoscale ligand. This alteration facilitates the study of a largescale drying transition. We investigate molecular-scale hydrodynamic effects and the rate constants for binding and develop a theoretical framework to describe hydrophobic assembly. This theory couples the diffusive reaction coordi...